Combination of a selective cyclooxygenase-2 inhibitor with epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 and protein kinase A antisense causes cooperative antitumor and antiangiogenic effect.
ABSTRACT Epidermal growth factor receptor (EGFR) and protein kinase A type I(PKAI) play an important role in the control of cancer cell growth and angiogenesis. Inhibitors of EGFR and PKAI have antitumor activity in vitro and in vivo in a variety of tumor types, and some of these agents are active after oral administration. Increasing evidence shows that cyclooxygenase (COX)-2 also plays a role in promoting cancer cell proliferation and angiogenesis. COX-2 expression can be induced by EGFR activation and is regulated by cAMP and PKA. Combination of an EGFR inhibitor with a nonselective COX-1/COX-2 inhibitor prevents the development of intestinal cancer in nude mice. Therefore, we investigated whether any cooperative antitumor effect can be obtained by the combined blockade of COX-2, EGFR, and PKAI.
The COX-2 inhibitor SC-236 was combined with the selective EGFR tyrosine kinase inhibitor ZD1839 (Iressa) and the DNA/RNA-mixed backbone oligonucleotide AS-PKAI to study their effect on human cancer growth and angiogenesis, measuring vascular endothelial growth factor (VEGF) and basic fibroblast growth factor expression and vessel formation, in vitro and after oral administration of these agents in mice.
A cooperative effect was observed with SC-236 in combination with either ZD1839 or AS-PKAI, as well as with all three agents together, on the proliferation of human colon and breast cancer cells in soft agar at doses that were ineffective for each agent alone. The antiproliferative effect was accompanied by inhibition of COX-2 expression. Moreover, combination of SC-236 with either agent or the triple combination markedly reduced VEGF secretion in the conditioned medium and completely suppressed VEGF and basic fibroblast growth factor expression. In nude mice bearing human colon cancer xenografts, a low, noninhibitory dose of SC-236 with ZD1839 and AS-PKAI, all given p.o., caused a dramatic cooperative antitumor effect, with no histological evidence of tumor in 60% of mice 5 weeks after treatment withdrawal, at which time all mice were alive. Moreover, analysis of tumor specimens revealed inhibition of vessel formation and expression of COX-2 and VEGF.
This is the first demonstration that three novel agents blocking multiple signaling pathways, in absence of cytotoxic drugs, may have a potent antitumor and antiangiogenic activity after oral administration. Because all agents are under clinical evaluation, our results provide a rationale to translate this feasible therapeutic strategy into a clinical setting.
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ABSTRACT: Conventional therapy for non-small cell lung cancer (NSCLC) has reached a plateau in increasing patient survival and overall prognosis still remains dismal. Advances in the knowledge of molecular events governing oncogenesis has led to a number of novel agents targeting specific pathways critical for tumour growth and survival. In the present paper we have thoroughly reviewed the existing evidence of novel agents currently studied in clinical trials, focusing on epidermal growth factor receptor family inhibitors, angiogenesis inhibitors, cyclooxygenase-2 inhibitors, Bcl-2 targeted agents, protein kinase C inhibitors, proteasome inhibitors, farnesyl transferase inhibitors and retinoids. Although erlotinib monotherapy in the second or third line setting and bevacizumab combined with conventional chemotherapy as a frontline therapy manage to prolong the life of patients with NSCLC, there is still much to be learned about the proper design of clinical trials and the selection of patient population enrolled in them. Multi-targeted therapy still remains the most attractive avenue for future treatment strategies.Current pharmaceutical design 02/2007; 13(27):2810-31. · 4.41 Impact Factor
Article: Protein Kinase A in Cancer[show abstract] [hide abstract]
ABSTRACT: In the past, many chromosomal and genetic alterations have been examined as possible causes of cancer. However, some tumors do not display a clear molecular and/or genetic signature. Therefore, other cellular processes may be involved in carcinogenesis. Genetic alterations of proteins involved in signal transduction have been extensively studied, for example oncogenes, while modifications in intracellular compartmentalization of these molecules, or changes in the expression of unmodified genes have received less attention. Yet, epigenetic modulation of second messenger systems can deeply modify cellular functioning and in the end may cause instability of many processes, including cell mitosis. It is important to understand the functional meaning of modifications in second messenger intracellular pathways and unravel the role of downstream proteins in the initiation and growth of tumors. Within this framework, the cAMP system has been examined. cAMP is a second messenger involved in regulation of a variety of cellular functions. It acts mainly through its binding to cAMP-activated protein kinases (PKA), that were suggested to participate in the onset and progression of various tumors. PKA may represent a biomarker for tumor detection, identification and staging, and may be a potential target for pharmacological treatment of tumors.Cancers. 01/2011;
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ABSTRACT: High expression of the epidermal growth factor receptor (EGFR) family confers a growth advantage on malignant cells in various tumor types. Most pancreatic cancers express EGFR, which seems to play an important role in the acquisition of aggressive clinical behaviour and in tumor invasion. Iressa (ZD1839), a quinazoline tyrosine kinase inhibitor selective for the EGF receptor, has shown good anti-tumor activity in both preclinical and clinical studies. Using two pancreatic cancer cell lines that express different EGFR and ErbB-2 levels, we analyzed the activity of Iressa and evaluated its modulation effect on four conventional cytotoxic drugs: gemcitabine, oxaliplatin, docetaxel and SN38. Iressa was tested at scalar doses up to the plasma peak level concentration and showed a similar weak cytostatic effect in both cell lines. Conversely, an additive or weak synergistic effect was observed when the drug was administered simultaneously with or following cytotoxic drugs. Our data show that Iressa has only a weak activity at doses within the plasmatic peak concentration and that its effect is independent of EGFR and p42/p44 expression and phosphorylation levels. This is in agreement with recent literature data that attribute an essential role to a specific EGFR mutation in mediating response to Iressa. This mutation was absent in both pancreatic cell lines tested.Cancer biology & therapy 11/2005; 4(10):1089-95. · 2.64 Impact Factor